Frailty is a clinical syndrome with symptoms as low body weight due to unintentional weight loss, exhaustion, weakness, slow walking and low physical activity. Frailty is characterized by a decreased reserve and resistance to stressors, in turn resulting from cumulative decline across multiple physiologic systems, and causing a vulnerability to adverse outcomes. Increased insulin resistance, metabolic syndrome and osteoporosis mount among these.
A widely used definition of this complex geriatric syndrome, as proposed by Fried et al. (2001) J Gerontol A Biol Sci Med Sci 56:M146-M156, is based on an assessment of five distinct characteristics. An individual is considered to be frail if they possess at least three of the following five characteristics: unintentional weight loss in the past year; weakness of grip strength; poor endurance/exhaustion; slowness; and low physical activity level.
Frailty has been associated with changes in biomarkers like IL-6, CRP, 25-OH-vitamin-D, IGF-1, D-dimers and is in particular prominent in elderly people. In the context of the invention, elderly particularly have an age of 60 or older, and more particularly of 65 or older.
Frailty is associated with a gradual loss of efficient protein metabolism. In turn this affects metabolic rates, leading to syndromes as mentioned above.
A major aspect of frailty is that it affects muscle mass and strength, leading to increased incidence of falls and associated injuries like fractures and impaired mobility. Together with muscle mass related lower immunity, reduced healing rates and mental deterioration, this leads to a loss of independency.
Currently, no treatment has been registered specifically for the treatment of frailty. Some clinical investigation has been done on the effect of various treatments on individual frailty symptoms. This includes, e.g., the effect of anabolic steroids on muscle mass, which is well known to the skilled person.
A reference on the effect of the anabolic steroid oxandrolone on muscle mass in elderly men, is Schroeder et al. 2005 J Gerontol A Biol Sci Med Sci 60:1586-1592.
Low serum 25-OH-vitamin-D concentrations, which is a marker for calcitriol shortage, are commonly found in the elderly and are found to accompany the development of frailty symptoms.
A reference that advocates vitamin D therapy is Campbell and Szoeke, Journal of Pharmacy Practice and Research, vol. 39, no. 2, June 2009, 147-151 provides an overview of alternative pharmacological treatments of frailty in the elderly. One such treatment is that with vitamin D, which is referred to in respect of its effects on bone, muscle and balance. Another such treatment is with anabolic hormones, but this treatment is said to have no clear benefit in the frail elderly.
A reference on emerging therapies to treat frailty syndrome in the elderly, is Cherniack et al., Alternative Medicine Review Volume 12, Number 3 2007, pages 246-258. Herein the focus is on nutritional supplementation with e.g. vitamins, carotenoids, creatine, DHEA, or beta-hydroxy-beta-methylbutyrate, and on exercise modalities (tai chi and cobblestone walking). Supplementation with vitamin D is referred to as a promising means to alleviate components of frailty syndrome. Also, with reference to the vitamin D deficiencies frequently occurring in the elderly, it is hypothesized that vitamin D supplementation might prevent frailty.
Combined treatment with nandrolone decanoate, oral alphacalcidol (Vitamin D3), and calcium supplementation in women recovering from hip fraction was shown to improve BMD, muscle mass and gait scores (Hedström et al. J Bone Joint Surg Br 2002; 84: 497-503). The document does not address frailty. Furthermore the subjects were living independently and had an average BMI status of 23 indicating that the subjects in this study were not frail. Whilst the study provides vitamin D in conjunction with the anabolic steroid, the disclosure, other than e.g. the Campbell et al. reference above, reflects the conventional wisdom in emphasizing the role of vitamin D in relation to bone, and the role of the anabolic steroid in relation to bone and muscle.
Efficient treatment of frailty symptoms is a real unmet medical need, given the way pathophysiology develops and associated health care cost increases.
In the alleviation and prevention of frailty symptoms, it is desired that more of the symptoms can be treated or prevented at the same time. In the treatment of frailty, it is desired to provide a single therapy that actually treats the condition, and particularly aims at improved functional capacity and independence, which are the preferred clinical end points for elderly patients. A typical consequence of frailty is that patients are subject to a downward spiral of decline, and will almost inevitably be headed towards admission into long-term care. It is desired to prevent and reverse the otherwise inevitable further decline and allow the patients to live independently for a longer period of time. This is particularly critical for patients that are in recovery after hospitalization, as this frequently is a turning point, in the frail elderly, leading to prolonged stays in a nursing homes (and further decline), rather than retaining independence (and regaining physical and mental activity, leading to improved health). Thus, medical intervention is needed.